A 38 year old male from a kindred with familial hyperalphalipoproteinemia was diabetic and normally ingested a diet extremely high in fat (55% calories) consisting of fried chicken wings and rum. Baseline lipids included TC = 278, TG = 62 and HDL levels ranging from 225-250 mg/dl. The effects of dietary fat and alcohol were investigated in the proband using the typical American diet (35% fat), high fat (55% fat) and high fat with alcohol (40%) diets. On the latter diet the proband was given rum daily with incremental increases of 2, 6, 9, 12, and 18 oz. every 2 weeks. Total cholesterol progressively increased on the 3 diets from 228 mg/dl to 350 mg/dl. Fasting TG averaged 110, 100 and 49 mg/dl on the 3 diets respectively. On the fat/alcohol diet lipoprotein lipase activity was increased 2 fold compared to controls. ApoB decreased from 86 to 63 mg/dl. ApoA-I increased to a peak of 536 mg/dl (nl 120+/-12 mg/dl) with no change in the apoA-II levels. HDL-C increased from 99 to 278 mg/dl. The metabolic basis of the increased HDL in the proband was evaluated using 125I-ApoA-I and 131I-apoA_II kinetics over 14d on both the American and high fat diet with 18oz of rum. On the American diet the apoA-I FCR was similar to controls (0.246 vs. 0.225d-1), however, the PR of the proband was increased 23.2 vs. 10.5 mg/d?gm of the controls. The FCR and PR of apoA-II were similar to controls. On the high fat diet with alcohol the FCR of apoA-I and apoA-II did not change while the PR of apoA-I increased dramatically to 41.1 mg/d?gm with no change in the apoA-II PR. The percent of LpA-I particles in HDL increased to 70% with alcohol. In summary: 1) Increased HDL was due to a dramatic selective increased synthesis of apoA-I. 2) The addition of alcohol to the high fat diet increased LpA-I particles synthesis and stimulated lipase activity leading to further increased HDL and decreased TG levels.